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HDAC2 negatively regulates memory formation and synaptic plasticity - PubMed

  • ️Thu Jan 01 2009

HDAC2 negatively regulates memory formation and synaptic plasticity

Ji-Song Guan et al. Nature. 2009.

Abstract

Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.

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Figures

Figure 1
Figure 1. HDAC2, but not HDAC1, overexpression mice exhibit impaired memory formation

a. Western blots from brain lysate showed up-regulation of HDAC1 and HDAC2 in HDAC1 and HDAC2 homozygous overexpression mice, respectively. b. Decreased histone acetylation in the hippocampus of HDAC1OE and HDAC2OE mice. c. Associative memory test for HDAC1OE and HDAC2OE mice. HDAC1OE mice (n=17), WT mice (n=19), HDAC2OE mice (n=14). d. Distance traveled during the initial 3 min exposure to the training box. e. The velocity during the training and electoral foot shock (I=1.0 mA). f. Hidden platform of Morris water maze. Escape latencies of WT mice improved significantly faster than HDAC2OE mice (Genotype x Day F(1,8)=3.401, p=0.0010; genotype F(1,8)=52.32, p<0.0001; Day F(1,8)=7.372, p<0.0001), but not HDAC1OE mice(Genotype x Day F(1,8)=0.5989, p=0.7784; Day F(1,8)=12.14, p<0.0001; Genotype F(1,8)=0.2672, p=0.6057) g. Representative path tracings of the probe test on day 5. The swimming time in each quadrant were quantified. T, target quadrant; L, left quadrant; O, opposite quadrant; R, right quadrant. *, p<0.05; **, p<0.005; ***, p<0.001.

Figure 2
Figure 2. HDAC2 knockout mice exhibit enhanced memory formation

a. Immunohistochemical images showed the HDAC2 expression in the hippocampus of WT mice but not HDAC2KO mice. scale bar, 100μm b. Samples from hippocampal histone extraction showed the histone acetylation level changes in HDAC2KO mice. c. Freezing behaviour of HDAC2KO mice and control littermates (HDAC2 −/−, n = 9; WT, n = 11) during the contextual and tone-dependent memory test. d. Distance traveled during the initial 3 min exposure to the training box. e. Velocity during the training and the electric foot shock (I=0.8 mA). **, p<0.005.

Figure 3
Figure 3. HDAC2 regulates synapse formation and plasticity in mouse hippocampus

a. Representative images of golgi staining from CA1 region of hippocampus. WT (n=23), HDAC2OE (n=21), HDAC2KO (n=27). Yellow arrowhead points to the spines. Scale bar, 10μm. b. Representative confocal images of synaptophysin (SVP)-immunoreactive signal on CA1. Py, pyramidal neuron layer; s.r. stratum radiatum. scale bar, 50μm (HDAC2KO, n=17; WT, n=25; HDAC2OE, n=21). *, p<0.05; **, p<0.005; ***, p<0.001 c. LTP was induced by two HFS (2 × 100Hz, 1s) in CA1 region from 6 month old HDAC2OE mice or their WT littermates. By 40 min, the fEPSPs from HDAC2OE mice decayed to baseline (103.1± 1.8 % compared with baseline) whereas fEPSPs from control mice remained potentiated (137.9 ± 6.8 % compared with baseline). d. LTP was induced by one HFS in the CA1 region from HDAC2KO mice or their WT littermates. Slices from WT mice showed a transient potentiation that decayed to baseline (n = 6 slice, 102.9± 4.5 % compared with baseline), 40 min after induction, whereas slices from HDAC2KO mice showed a robust potentiation (n = 8 slice 144.1 ± 2.0 % compared with baseline). Inserts in c and d show superimposed sample sweeps from the first 5 min (black) and last 5 min (red) of the recording.

Figure 4
Figure 4. HDAC2 but not HDAC1 binds to promoters of memory related genes

a. Semi-quantitative PCR from ChIP of samples showed specificity of DNA-binding for HDAC2 and HDAC1 quantified according to the real-time PCR signal (n=3). b. Histone acetylation changes in specific gene promoter regions in HDAC1OE, HDAC2OE and HDAC2KO mice brain. Fragmented chromatin was immunoprecipitated with antibody recognizing acetylated histone 3 or histone 4 and quantified with real-time PCR. c. Nuclear extracts prepared from the WT or HDAC2KO mouse brain were immunoprecipitated to evaluate the association of HDAC1/2 with co-repressors.

Figure 5
Figure 5. SAHA, an HDAC inhibitor, improves associative learning by targeting HDAC2

a. Memory test for mice with contextual fear conditioning training (foot shock 1.0 mA). HDAC2OE mice (n=12, each group) and WT littermates (SAHA group, n=12; saline group, n=15) were treated with saline or SAHA (25mg/kg, i.p.) for 10 days before memory test. b. Immunostaining images of CA1 region from WT and HDAC2OE mice received chronic SAHA treatment or saline treatment. Py, pyramidal neuron layer; s.r., stratum radiatum, Scale bar=50μm, (n=12 for each group). c. Images of Golgi staining from CA1 region of hippocampus. For WT, naïve, n=23; SAHA, n=41; for HDAC2OE, naïve, n=21; SAHA, n=32. Scale bar: 10μm. d. Memory tests for mice with contextual fear conditioning training (foot shock 0.5 mA) after 10-day SAHA injection (25mg/kg, i.p.). WT mice (n=10, each group) and HDAC2 KO mice (n=8, each group). e. Immunostaining images of CA1 region from HDAC2KO mice received chronic SAHA treatment or saline treatment. Saline, n=15; SAHA, n=22. Scale bar=50μm. f. Images of Golgi staining of CA1 region from HDAC2KO mice. HDAC2KO, SAHA, n=24; naïve, n=27. *, p<0.05; **, p<0.005; ***, p<0.001

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